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p110δ PI3 kinase pathway: emerging roles in cancer.

Tzenaki N, Papakonstanti EA - Front Oncol (2013)

Bottom Line: A wealth of knowledge has come from studies showing the central role of p110δ PI3K in B-cell functions and B-cell malignancies.Further data have documented that wild-type p110δ becomes oncogenic when overexpressed in cell culture models and that p110δ is the predominant isoform expressed in some human solid tumor cells playing a prominent role in these cells.Genetic inactivation of p110δ in mice models and highly-selective inhibitors of p110δ have demonstrated an important role of this isoform in differentiation, growth, survival, motility, and morphology with the inositol phosphatase PTEN to play a critical role in p110δ signaling.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, School of Medicine, University of Crete Heraklion, Greece.

ABSTRACT
Class IA PI3Ks consists of three isoforms of the p110 catalytic subunit designated p110α, p110β, and p110δ which are encoded by three separate genes. Gain-of-function mutations on PIK3CA gene encoding for p110α isoform have been detected in a wide variety of human cancers whereas no somatic mutations of genes encoding for p110β or p110δ have been reported. Unlike p110α and p110β which are ubiquitously expressed, p110δ is highly enriched in leukocytes and thus the p110δ PI3K pathway has attracted more attention for its involvement in immune disorders. However, findings have been accumulated showing that the p110δ PI3K plays a seminal role in the development and progression of some hematologic malignancies. A wealth of knowledge has come from studies showing the central role of p110δ PI3K in B-cell functions and B-cell malignancies. Further data have documented that wild-type p110δ becomes oncogenic when overexpressed in cell culture models and that p110δ is the predominant isoform expressed in some human solid tumor cells playing a prominent role in these cells. Genetic inactivation of p110δ in mice models and highly-selective inhibitors of p110δ have demonstrated an important role of this isoform in differentiation, growth, survival, motility, and morphology with the inositol phosphatase PTEN to play a critical role in p110δ signaling. In this review, we summarize our understanding of the p110δ PI3K signaling pathway in hematopoietic cells and malignancies, we highlight the evidence showing the oncogenic potential of p110δ in cells of non-hematopoietic origin and we discuss perspectives for potential novel roles of p110δ PI3K in cancer.

No MeSH data available.


Related in: MedlinePlus

p110δ PI3K mediates the effects of CSF-1 or EGF via RhoA and PTEN in macrophages and some solid tumor cells. Activation of p110δ leads to increased activity of p190RhoGAP (through PYK2/Src activation) and to cytoplasmic accumulation of p27 (which is mediated by the increased Akt activity). p190RhoGAP induces the inactivation of RhoA whereas p27 prevents the activation of RhoA both thus leading to reduced RhoA activity and consequently to decreased PTEN activity. Inactivation of p110δ by IC87114 reverses these pathways leading to PTEN activation which then opposes the PI3K reaction of the remaining active p110 isoforms. The p190RhoGAP-driven mechanism almost solely keeps RhoA activity low under basal whereas that of p27 contributes upon stimulated conditions. Arrows with dashed lines represent alterations in activity or location in the presence (red) or in the absence (black) of IC87114.
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Figure 4: p110δ PI3K mediates the effects of CSF-1 or EGF via RhoA and PTEN in macrophages and some solid tumor cells. Activation of p110δ leads to increased activity of p190RhoGAP (through PYK2/Src activation) and to cytoplasmic accumulation of p27 (which is mediated by the increased Akt activity). p190RhoGAP induces the inactivation of RhoA whereas p27 prevents the activation of RhoA both thus leading to reduced RhoA activity and consequently to decreased PTEN activity. Inactivation of p110δ by IC87114 reverses these pathways leading to PTEN activation which then opposes the PI3K reaction of the remaining active p110 isoforms. The p190RhoGAP-driven mechanism almost solely keeps RhoA activity low under basal whereas that of p27 contributes upon stimulated conditions. Arrows with dashed lines represent alterations in activity or location in the presence (red) or in the absence (black) of IC87114.

Mentions: Recent data documented that p110δ PI3K inhibits the activity of the PTEN tumor suppressor via a negative signaling pathway that involves inhibition of RhoA/ROCK (Papakonstanti et al., 2007) (Figure 4). The activation of p110δ PI3K was found to positively regulate the p190RhoGAP activity and to result in the accumulation of p27 in the cytoplasm (Papakonstanti et al., 2007). Given that p190RhoGAP catalyzes the return of RhoA-GTP (active state) to RhoA-GDP (inactive state) (Bernards and Settleman, 2005) and p27 prevents the return of RhoA-GDP to RhoA-GTP (Besson et al., 2004) the activation of p110δ leads to decreased RhoA activity and consequently to decreased PTEN activity. Upon genetic or pharmacological inactivation of p110δ by IC87114, PTEN becomes activated and dampens the PI3K pathway (Figure 4). The isoform-selective role of p110δ in the negative regulation of RhoA and the mechanism by which RhoA regulates PTEN activity under the control of p110δ are not currently understood but it seems that these are related with activation of p110δ at certain cellular compartments (Papakonstanti, unpublished data). This feedback mechanism was originally found to be the case in primary (Papakonstanti et al., 2007) and transformed macrophages (Papakonstanti et al., 2008) and in mouse brain tissue (Eickholt et al., 2007). More recently we showed that the negative regulation of PTEN by p110δ is also the case in those cancer contexts where p110δ is expressed at high levels (Tzenaki et al., 2012). The p110δ protein was found to be expressed at different levels in different cancer types e.g., the p110δ PI3K is the predominant isoform expressed in human primary breast carcinoma, whereas ovarian and cervical human carcinomas mainly express p110α and p110β (Tzenaki et al., 2012). The activity of wild-type PTEN was found to be suppressed in breast and prostate cancer cells that express high levels of p110δ suggesting that the elevated expression of p110δ might provide these cells with a competitive advantage to keep their wild-type PTEN inactive (Tzenaki et al., 2012). Breast and prostate cancer cells expressing functional PTEN were also sensitive to anti-proliferative effect of p110δ inhibitors through PTEN activation. In contrast, inhibition of p110δ in ovarian and cervical cancer cells which express very low levels of p110δ had no effect neither in PTEN activity nor in cell proliferation (Tzenaki et al., 2012).


p110δ PI3 kinase pathway: emerging roles in cancer.

Tzenaki N, Papakonstanti EA - Front Oncol (2013)

p110δ PI3K mediates the effects of CSF-1 or EGF via RhoA and PTEN in macrophages and some solid tumor cells. Activation of p110δ leads to increased activity of p190RhoGAP (through PYK2/Src activation) and to cytoplasmic accumulation of p27 (which is mediated by the increased Akt activity). p190RhoGAP induces the inactivation of RhoA whereas p27 prevents the activation of RhoA both thus leading to reduced RhoA activity and consequently to decreased PTEN activity. Inactivation of p110δ by IC87114 reverses these pathways leading to PTEN activation which then opposes the PI3K reaction of the remaining active p110 isoforms. The p190RhoGAP-driven mechanism almost solely keeps RhoA activity low under basal whereas that of p27 contributes upon stimulated conditions. Arrows with dashed lines represent alterations in activity or location in the presence (red) or in the absence (black) of IC87114.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3585436&req=5

Figure 4: p110δ PI3K mediates the effects of CSF-1 or EGF via RhoA and PTEN in macrophages and some solid tumor cells. Activation of p110δ leads to increased activity of p190RhoGAP (through PYK2/Src activation) and to cytoplasmic accumulation of p27 (which is mediated by the increased Akt activity). p190RhoGAP induces the inactivation of RhoA whereas p27 prevents the activation of RhoA both thus leading to reduced RhoA activity and consequently to decreased PTEN activity. Inactivation of p110δ by IC87114 reverses these pathways leading to PTEN activation which then opposes the PI3K reaction of the remaining active p110 isoforms. The p190RhoGAP-driven mechanism almost solely keeps RhoA activity low under basal whereas that of p27 contributes upon stimulated conditions. Arrows with dashed lines represent alterations in activity or location in the presence (red) or in the absence (black) of IC87114.
Mentions: Recent data documented that p110δ PI3K inhibits the activity of the PTEN tumor suppressor via a negative signaling pathway that involves inhibition of RhoA/ROCK (Papakonstanti et al., 2007) (Figure 4). The activation of p110δ PI3K was found to positively regulate the p190RhoGAP activity and to result in the accumulation of p27 in the cytoplasm (Papakonstanti et al., 2007). Given that p190RhoGAP catalyzes the return of RhoA-GTP (active state) to RhoA-GDP (inactive state) (Bernards and Settleman, 2005) and p27 prevents the return of RhoA-GDP to RhoA-GTP (Besson et al., 2004) the activation of p110δ leads to decreased RhoA activity and consequently to decreased PTEN activity. Upon genetic or pharmacological inactivation of p110δ by IC87114, PTEN becomes activated and dampens the PI3K pathway (Figure 4). The isoform-selective role of p110δ in the negative regulation of RhoA and the mechanism by which RhoA regulates PTEN activity under the control of p110δ are not currently understood but it seems that these are related with activation of p110δ at certain cellular compartments (Papakonstanti, unpublished data). This feedback mechanism was originally found to be the case in primary (Papakonstanti et al., 2007) and transformed macrophages (Papakonstanti et al., 2008) and in mouse brain tissue (Eickholt et al., 2007). More recently we showed that the negative regulation of PTEN by p110δ is also the case in those cancer contexts where p110δ is expressed at high levels (Tzenaki et al., 2012). The p110δ protein was found to be expressed at different levels in different cancer types e.g., the p110δ PI3K is the predominant isoform expressed in human primary breast carcinoma, whereas ovarian and cervical human carcinomas mainly express p110α and p110β (Tzenaki et al., 2012). The activity of wild-type PTEN was found to be suppressed in breast and prostate cancer cells that express high levels of p110δ suggesting that the elevated expression of p110δ might provide these cells with a competitive advantage to keep their wild-type PTEN inactive (Tzenaki et al., 2012). Breast and prostate cancer cells expressing functional PTEN were also sensitive to anti-proliferative effect of p110δ inhibitors through PTEN activation. In contrast, inhibition of p110δ in ovarian and cervical cancer cells which express very low levels of p110δ had no effect neither in PTEN activity nor in cell proliferation (Tzenaki et al., 2012).

Bottom Line: A wealth of knowledge has come from studies showing the central role of p110δ PI3K in B-cell functions and B-cell malignancies.Further data have documented that wild-type p110δ becomes oncogenic when overexpressed in cell culture models and that p110δ is the predominant isoform expressed in some human solid tumor cells playing a prominent role in these cells.Genetic inactivation of p110δ in mice models and highly-selective inhibitors of p110δ have demonstrated an important role of this isoform in differentiation, growth, survival, motility, and morphology with the inositol phosphatase PTEN to play a critical role in p110δ signaling.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, School of Medicine, University of Crete Heraklion, Greece.

ABSTRACT
Class IA PI3Ks consists of three isoforms of the p110 catalytic subunit designated p110α, p110β, and p110δ which are encoded by three separate genes. Gain-of-function mutations on PIK3CA gene encoding for p110α isoform have been detected in a wide variety of human cancers whereas no somatic mutations of genes encoding for p110β or p110δ have been reported. Unlike p110α and p110β which are ubiquitously expressed, p110δ is highly enriched in leukocytes and thus the p110δ PI3K pathway has attracted more attention for its involvement in immune disorders. However, findings have been accumulated showing that the p110δ PI3K plays a seminal role in the development and progression of some hematologic malignancies. A wealth of knowledge has come from studies showing the central role of p110δ PI3K in B-cell functions and B-cell malignancies. Further data have documented that wild-type p110δ becomes oncogenic when overexpressed in cell culture models and that p110δ is the predominant isoform expressed in some human solid tumor cells playing a prominent role in these cells. Genetic inactivation of p110δ in mice models and highly-selective inhibitors of p110δ have demonstrated an important role of this isoform in differentiation, growth, survival, motility, and morphology with the inositol phosphatase PTEN to play a critical role in p110δ signaling. In this review, we summarize our understanding of the p110δ PI3K signaling pathway in hematopoietic cells and malignancies, we highlight the evidence showing the oncogenic potential of p110δ in cells of non-hematopoietic origin and we discuss perspectives for potential novel roles of p110δ PI3K in cancer.

No MeSH data available.


Related in: MedlinePlus